Characterization of Mesenchymal Stem Cells Derived from Bisphosphonate-Related Osteonecrosis of the Jaw Patients' Gingiva

Mengyu Li; Jiajia Wang; Yejia Yu; Yuqiong Zhou; Yueqi Shi; Wenjie Zhang; Geehun Son; Jing Ge; Jun Zhao; Chi Yang; Shaoyi Wang

doi:10.1007/s12015-021-10241-8

Characterization of Mesenchymal Stem Cells Derived from Bisphosphonate-Related Osteonecrosis of the Jaw Patients' Gingiva

Stem Cell Rev Rep. 2022 Jan;18(1):378-394. doi: 10.1007/s12015-021-10241-8. Epub 2021 Sep 22.

Authors

Mengyu Li^#¹, Jiajia Wang^#¹, Yejia Yu¹, Yuqiong Zhou¹, Yueqi Shi¹, Wenjie Zhang², Geehun Son³, Jing Ge³, Jun Zhao⁴, Chi Yang⁵, Shaoyi Wang⁶

Affiliations

¹ Department of Oral Surgery, Shanghai Engineering Research Centre of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Centre for Oral Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Prosthodontics, Shanghai Engineering Research Centre of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Centre for Oral Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Centre for Oral Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Orthodontics, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Centre for Oral Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Centre for Oral Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yangchi63@hotmail.com.
⁶ Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Centre for Oral Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. wangshaoyi163@aliyun.com.

^# Contributed equally.

Abstract

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition that specifically occurs in the oral cavity, characterized by retarded wound healing in oral mucosa accelerating the exposure of bone. Moreover, the pathological mechanism remains poorly understood. Gingival mesenchymal stem cells (GMSCs) play a critical role in gingival healing and soft tissue regeneration. Although previous studies have showed that bisphosphonates (BPs) are highly toxic to healthy GMSC, there is overall lack of direct evidence demonstrating the characterization of GMSCs derived from BRONJ patients. In present study, we isolated GMSCs for the first time from the central area of BRONJ patients' gingiva (center-BRONJ GMSCs) and the peripheral area (peri-BRONJ GMSCs), and found that they exhibited decreased proliferation, adhesion, migration capacities and underwent early apoptosis in vitro compared control GMSCs. Notably, the central and peripheral BRONJ GMSCs transplantation in a mice excisional skin model also displayed lower cell survival rate and poor healing effects than that of controls. Mechanistically, TGF-β1 signaling pathway was suppressed not only in BRONJ patients' gingival lesions but also in BRONJ GMSCs transplantation animal model. The results above suggested that under the microenvironment of BRONJ patients, the dysfunction of GMSCs and the suppressed TGF-β1 signaling pathway may be the vital factors in impaired gingival healing, thus contributing to persistent exposure of underlying bone and development of BRONJ. This study provides new insights into the prevention for BRONJ by improving the functions of GMSCs and upregulating TGF-β1 in accelerating gingival wound healing. Schematic illustration of the dysfunction of BRONJ GMSCs in vitro and BRONJ GMSCs transplantation in a mice skin model delaying cutaneous wound healing mainly via suppressing TGF-β1 signaling pathway.

Keywords: Bisphosphonates; Gingival mesenchymal stem cells; Microenvironment; Oral mucosa; Osteonecrosis; Transplantation; Wound healing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bisphosphonate-Associated Osteonecrosis of the Jaw* / drug therapy
Bisphosphonate-Associated Osteonecrosis of the Jaw* / metabolism
Disease Models, Animal
Gingiva
Humans
Mesenchymal Stem Cell Transplantation* / methods
Mesenchymal Stem Cells*
Mice
Transforming Growth Factor beta1 / metabolism

Substances

Transforming Growth Factor beta1